P2Y13 Receptor Regulates HDL Metabolism and Atherosclerosis In Vivo

High-density lipoprotein (HDL) is known to protect against atherosclerosis by promoting the reverse cholesterol transport. A new pathway for the regulation of HDL-cholesterol (HDL-c) removal involving F1-ATPase and P2Y13 receptor (P2Y13R) was described in vitro, and recently in mice. However, the physiological role of F1-ATPase/P2Y13R pathway in the modulation of vascular pathology i.e. in the development of atherosclerotic plaques is still unknown. We designed a specific novel agonist (CT1007900) of the P2Y13R that caused stimulation of bile acid secretion associated with an increased uptake of HDL-c in the liver after single dosing in mice. Repeated dose administration in mice, for 2 weeks, stimulated the apoA-I synthesis and formation of small HDL particles. Plasma samples from the agonist-treated mice had high efflux capacity for mobilization of cholesterol in vitro compared to placebo group. In apoE^−/− mice this agonist induced a decrease of atherosclerotic plaques in aortas and carotids. The specificity of P2Y13R pathway in those mice was assessed using adenovirus encoding P2Y13R-shRNA. These results demonstrate that P2Y13R plays a pivotal role in the HDL metabolism and could also be a useful therapeutic agent to decrease atherosclerosis. In this study, the up-regulation of HDL-c metabolism via activation of the P2Y13R using agonists could promote reverse cholesterol transport and promote inhibition of atherosclerosis progression in mice.     

Role of Altered Expression,Activity and Sub-cellular Distribution of Various Histone Deacetylases (HDACs) in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis

Cellular and Molecular Neurobiology - Histone deacetylases (HDACs) have been described to have both neurotoxic and neuroprotective roles, and partly, depend on its sub-cellular distribution. HDAC...     

Effect of SOD1 overexpression on age- and noise-related hearing loss

Reactive oxygen species (ROS) have been implicated in hearing loss associated with aging and noise exposure. Superoxide dismutases (SODs) form a first line of defense against damage mediated by the superoxide anion, the most common ROS. Absence of Cu/Zn SOD (SOD1) has been shown to potentiate hearing loss related to noise exposure and age. Conversely, overexpression of SOD1 may be hypothesized to afford a protection from age- and noise-related hearing loss. This hypothesis may be tested using a transgenic mouse model carrying the human SOD1 gene. Contrary to expectations, here, we report that no protection against age-related hearing loss was observed in mice up to 7 months of age or from noise-induced hearing loss when 8 week old mice were exposed to broadband noise (4-45 kHz, 110 dB for 1 h). Mitochondrial DNA deletion, an index of aging, was elevated in the acoustic nerve of transgenic mice compared to nontransgenic littermates. The results indicate the complexity of oxidative metabolism in the cochlea is greater than previously hypothesized.     

Detection of a nafenopin-binding protein in rat liver cytosol associated with the induction of peroxisome proliferation by hypolipidemic compounds

[3H]nafenopin, a known inducer of liver peroxisomal enzymes, was shown to bind to a specific, saturable pool of binding sites in cytosols from rat liver and kidney cortex. Tissue levels of this binding protein (liver greater than kidney cortex; not detectable in myocardium, skeletal muscle) were seen to correlate with the ability of nafenopin to induce peroxisomal enzymes in these organs. Clofibrate and ciprofibrate, which are structurally similar to nafenopin, competitively blocked the specific binding of [3H]nafenopin. Phenobarbital, a non-inducer of peroxisomes, and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid and 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio(N-beta-hydroxyethyl)acetamide, which are structurally unrelated peroxisome proliferators, did not complete for the specific [3H]nafenopin binding sites. The [3H]nafenopin binding protein is proposed as a mediator of the drug-induced increase in peroxisomes and associated peroxisomal enzymes.     

A new nonsyndromic X-linked sensorineural hearing impairment linked to Xp21.2.

X-linked deafness is a rare cause of hereditary hearing impairment. We have identified a family with X-linked dominant sensorineural hearing impairment, characterized by incomplete penetrance and variable expressivity in carrier females, that is linked to the Xp21.2, which contains the Duchenne muscular dystrophy (DMD) locus. The auditory impairment in affected males was congenital, bilateral, profound, sensorineural, affecting all frequencies, and without evidence of radiographic abnormality of the temporal bone. Adult carrier females manifested bilateral, mild-to-moderate high-frequency sensorineural hearing impairment of delayed onset during adulthood. Eighteen commercially available, polymorphic markers from the X chromosome, generating a 10-15-cM map, were initially used for identification of a candidate region. DXS997, located within the DMD gene, generated a two-point LOD score of 2.91 at theta = 0, with every carrier mother heterozygous at this locus. Recombination events at DXS992 (located within the DMD locus, 3' to exon 50 of the dystrophin gene) and at DXS1068 (5' to the brain promoter of the dystrophin gene) were observed. No recombination events were noted with the following markers within the DMD locus: 5'DYS II, intron 44, DXS997, and intron 50. There was no clinical evidence of Duchenne or Becker muscular dystrophy in any family member. It is likely that this family represents a new locus on the X chromosome, which when mutated results in nonsyndromic sensorineural hearing loss and is distinct from the heterogeneous group of X-linked hearing losses that have been previously described.